Design
and Evaluation of Mucoadhesive Tablets of Lorsatan Potassium
V Ganesan1,
Nilesh P Tekade2*, Nitin
S Bhajipale2, Durgesh R Dewade2
and Raju R Thenge3
1Swami Vivekananda College of Pharmacy,
Elayampalayam-637 205, Tiruchengode, Namakkal, Tamilnadu
2S.G.S.P.S.
Institute of Pharmacy, Kaulkhed, Akola 444004,
Maharashtra, India.
3I.B.S.S
College of Pharmacy, Malkapur 443101,
Buldana, Maharashtra, India.
ABSTRACT
Mucoadhesive tablets of
Lorsatan Potassium were prepared using carbopol-940P,
Sodium carboxy methyl cellulose (SCMC), hydroxy propyl methyl cellulose
(HPMC), ethyl cellulose (EC) and Eudragit-RL100 as mucoadhesive
polymers. Eight formulations were developed with varying concentrations of
polymers. The SCMC is used as a primary polymer because of its excellent mucoadhesive property and secondary polymers like HPMC, EC,
Carbopol-940P and Eudragit RL-100 were used. The formulations were evaluated for in-vitro
drug release, in-vitro swelling studies and in-vitro bioadhesive
strength studies. Formulation R-03 showed maximum release of 95.68% in 10hours
and maximum swelling index of 99.59 % after 10hours, also showed highest bioadhesion. FTIR
studies show no evidence on interaction between drug and polymers. The results
indicate that suitable mucoadhesive tablets with
desired properties could be prepared.
Keywords: Mucoadhesive tablets, Losartan
Potassium, Swelling index, FT-IR, Drug release
INTRODUCTION:
Mucoadhesion can be
defined as the ability of a synthetic or biological material to adhere (stick)
to mucosa or mucus for an extended period of time. For Mucoadhesion to
occur, first an intimate contact must exist between the mucoadhesive
polymer and the mucosa. After the
contact is established, the most important process is interpenetration of
polymer chains with those of the mucus.1 Hence can be used for
targeting a drug to particular region of the body for extended periods of
time. A bioadhesive
system plays a major role in this field, due to its potential. Besides acting as platforms for sustained
release dosage forms, bioadhesive polymers can
themselves exert some control over the rate and amount of drug release and thus
contribute to the therapeutic efficacy of bioadhesive
drug delivery system2.
Many of
these delivery routes, particularly those through the nasal, ocular,
reproductive and gastrointestinal system, involve contact with mucosal
surfaces. The gastrointestinal route has been particularly popular among
medical staff and patients alike3.
Although convenient, unfortunately, this route can be very inefficient
for a number of reasons, including too rapid transit of the drug-containing
delivery system (powder, tablet, suspension, capsule etc.). Past the optimum
site for absorption, which is normally the small intestine and to a lesser
degree the stomach and colon. Resolution
of this problem would be particularly important in the case of
controlled-release drug delivery systems, designed to deliver drugs over
extended periods of time (12-24 Hrs)4
Losartan Potassium
an antihypertensive agent having half life about 2 hrs. when given as high
single dosage produce high discomfort such as marked flushing, diarrhoea and itching to the patients.5,6 Hence
to sustain the release as well as to reduce discomfort to the patient,7.8
. Losartan Potassium mucoadhesive
tablets were designed. For studying the effects of various mucoadhesive
polymers, the formulations were designed in a manner that all the polymers were
kept bound with sodium CMC to optimize the combined effect of them. The present
study aimed to design and evaluate Losartan Potassium
mucoadhesive tablet using various polymer such as carbopol 940P, SCMC, HPMC , Eudragit
RL100 and ethyl cellulose.
MATERIALS
AND METHODS:
Materials:
Losartan Potassium
was gift sample from Emcure Pharmaceuticals Pvt.
Ltd., Pune., Carbopol-940P by S.D.Fine
chemicals Ltd, Mumbai.Eudragit RL-100, HPMC, SCMC,
EC, Magnesium Stearate were obtained from Loba Chemie Pvt. Ltd,
Formulaton
of Mucoadhesive Tablets:
Mucoadhesive tablets of
Losartan Potassium were prepared by Direct
Compression using different polymers such as SCMC, HPMC, Carbopol
940P, Ethyl cellulose and Eudragit RL100. The different concentration of SCMC and other
polymers were used. Compositions of various formulations are shown in (Table
I). All the ingredients of the Mucoadhesive tablets
of Losartan Potassium was weighed and mixed in tray,
and blend was well mixed, then in the last magnesium stearate
and talc was added for lubrication and the blended material was compressed.(Rimek, Mumbai.)
Evaluation
of
Mucoadhesive Tablets9,10 :
a) Weight variation
test:
Twenty tablets of each
formulation were weighed individually using a digital electronic balance. The
average weight was calculated and individual tablet weight was compared with
the average value and the deviation was recorded.
b) Drug content
uniformity of tablets:
Ten tables from each
batch were weighed accurately and powdered equivalent to 50 mg of Losartan Potassium and shaken with water in 100 ml of
volumetric flask, dilute with water up to volume and mix. Transfer 2 ml of this solution to a 100 ml
volumetric flask, dilute with water to volume and mix. Resulting solution was filtered and the
absorbance of filtrate was recorded by using spectrophotometer at 205 nm and
content of Losartan Potassium was calculated.
c) Hardness and
friability:
Hardness values of
each formulation type were determined using Pfizer hardness tester. For this
the lower plunger was placed in contact with the tablet and a zero reading was
taken. The upper plunger was then forced against a spring by turning a
threaded bolt until the tablet fractured. The hardness was recorded from the
position of the pointer. Friability testing was done using Roche friabilator; twenty tablets of each formulation were
carefully dedusted and accurately weighed. These
tablets were placed in the rotating drum of the friabilator.
Drum was operated for the 100 revolutions. The tablets were removed and dedusted and reweighed. Percentage weight loss was
calculated.
Table IV : Bioadhesive Strength and Detachment Force
|
Formulation
|
Bioadhesive strength (gm)
|
Detachment
Force(N)
|
|
R-01
|
10.52±0.312
|
0.929
|
|
R-02
|
9.45±0.092
|
0.995
|
|
R-03
|
13.20±0.168
|
1.128
|
|
R-04
|
12.43±0.543
|
1.042
|
|
R-05
|
9.50±0.741
|
0.838
|
|
R-06
|
9.82±0.221
|
0.900
|
|
R-07
|
11.19±0.323
|
0.981
|
|
R-08
|
10.65±0.441
|
1.025
|
e) Thickness:
Five tablets were
selected randomly from each batch and thickness was measured by using Vernier caliper.
f)
In-Vitro Release Studies 11 :
In vitro release study
of mucoadhesive tablets of Losartan
Potassium was carried out using the USP I (Basket apparatus) method at 100
rpm. Medium used for release rate study
was 900 ml of buffer ( pH 7.4) solution. During the course of study whole
assembly was maintained at 37±0.2˚C.
1 ml withdrawn at specific time interval and replaced with same amount
of fresh medium ( pH 7.4). Volume of withdrawn sample was made up to 10ml in
volumetric flask .Then amount of Losartan Potassium
released was determined spectrophotometrically at 205 nm.
g)
In-Vitro Swelling Studies 12,13 :
The
tablets of each formulation were weighed individually (W1) and placed
separately in Petri-dishes containing 2% Agar gel. At regular intervals (1, 2,
3, 4, 5 hours) the tablets were removed from Petri dishes and excess water
removed carefully using filter paper. The swollen tablets were re-weighed (W2);
the swelling index of each formulation calculated by using this formula.
% Swelling Index (S.I.) = W1-W2 / W1x100
h) In-vitro Bioadhesion Study14,15
:
The two sides of the
balance were balanced with a 5gms weight on the right hand side. The goat intestine excised and washed was
tied tightly with the mucosal side upwards using thread over the protrusion in
the Teflon block. The block was then
lowered into the glass container, which was then filled with isotonic phosphate
buffer pH 7.4. Such that the buffer just reaches the surface of mucosal membrane
and keeps it moist. This was then kept
below the left hand set up of the balance.
The tablets was then stuck with a little moisture, on to the cylinder
hanging on the left hand side and the balanced beam raised with the 5gm weight
on the right pan removed. This lowered
the Teflon cylinder along with films over the mucosa, with a weight of 5gms.
The balance was kept in this position for 3 minutes and then slowly weights
were added on the right pan, till the tablet separated from the mucosal
surface. The excess weight on the right pan i.e. total weight minus 5gm is the
force required to separate the tablets from the mucosa. This gave the bioadhesive strength of the tablet in gms.
After each measurement the tissue was gently and thoroughly washed with isotonic
buffer pH 7.4 and left for 5 minutes before the next measurement. Care was
taken not to use a broken mucosa.
Figure I : In-vitro
drug release of various formulations
i) Detachment Force Measurement16,17
:
The Losartan Potassium tablet on one side with mucoadhesive polymer, and the in polymer matrix tablets
were prepared a fine hole drilled in the tablets to be tested with a fine
needle in the center. A thread was
passed through it and tied around the tablet.
The other end of the thread was tied to the single pan suspended from
the stand. The length of the tread is
such that in resting state the tablet should be at the middle of the intestinal
piece. After inserting the tablet into
the G.I.T. segment and lightly pressing the G.I.T. segment with tablet by a
forceps, the assembly should be kept undisturbed for a fixed time interval of
30 min. Then water was added with a
burette slowly drop by drop into the beaker.
The amount of water required to pull out the tablet from the intestinal
segment represents the force required to pull the tablet against the adhesion.
The force in Newton in
calculated by the equation.
F=
0.00981 W/2
Where; W- The amount of water.
j) FTIR
Study:
A physical mixture
(1:1) of drug and polymer was prepared and mixed with suitable quantity of
potassium bromide. About 100mg of this
mixture was compressed to form a transparent pellet using a hydraulic press at
10 tones pressure. It was scanned from
4000 to 400 cm-1 in a Perkin Elmer FTIR spectrophotometer. The IR spectrum of the physical mixture was
compared with those of pure drug and polymers.
RESULTS
AND DISCUSSION:
The mass
and thickness of tablets were within the limits of uniformity. The mass ranged
from 248.8±0.59 to 252.8±0.68mg. Thickness ranged between 5.7±0.173 to 6.45±0.129
mm . Hardness and friability of tablets were in the range of 6.25±0.2 to 8.0±1.and 0.196 to 0.806 % respectively. The
drug content in all batches were ranged
from 98.41 to 99.9%.(Table-II) The Release
of Losartan potassium from mucoadhesive
tablets varied according to type and ratio of matrix forming polymers . The
drug release was governed by amount of matrix forming polymers.
From the In vitro data
analysis shown in Figure-I, formulations R-01 to R-08 was showed that the R-01 comprising of SCMC and ethyl cellulose in ratio 1:2 and 2:1
respectively, R-02 released the drug
within 6hr. and was devoid of drug molecules. This can be attributed to the
higher swelling ability of SCMC and when swell it exerts intrapolymer
swelling force promoting the leaching of the drug out from the porous matrix.
The extensive swelling ability may be contributed due to presence of more
hydroxyl groups in SCMC molecules; hence it exhibited least retardant effect in
R-01 when SCMC was incorporated with
ethyl cellulose in the ratio 1:2, the release profile extended to 7hr., because
of increasing matrix density. This was
evidence from the t80% value obtained from the R-01 and R-02. When increasing the concentration of ethyl
cellulose, it increases the t80% value, but not in a proportionate
manner due to the lack of binding capacity of ethyl cellulose with drug
molecules. Then R-03 and R-04 was studied by changing polymer with carbopol 940P and results indicated that R-03 containing carbopol in ratio 1:2 produced a more retardant effect
since it is a synthetic high molecular weight polymer of acrylic acid with good
swelling ability and low leaching properties. But in R-04 as concentration of
SCMC increases, due to its high swellability and
higher disintegrating property it shows least drug release as compared to R-03.
This was indicated by the t80% value obtained from R-03 and R-04.
Then the R-05 and R-06 containing sodium CMC and HPMC in the ratio 1:2 and 2:1
respectively. It was evidenced that the R-06 shows some what faster drug
release as compared to R-05, But in R-05 drug release is in controlled manner
than R-06 because HPMC when dissolved in water increases viscosity due to which
polymer matrix becomes dense and thus shows release up to 8hr. which is evidenced
from t80% values obtained from R-05. Then Carbopol
940P substituted with Eudragit RL100 in R-07 and R-08
and the t80% values of above said formulations were found to be
equal to that of carbopol batches but slightly to
lesser extent. Even though it has comparative
less retardant ability of Losartan Potassium when
compared to Carbopol 940P.
All the mucoadhesive tablets were assessed for their swelling and
the result are shown in the Table-III. The descending order of swelling for the
formulation according to the swelling index was, SCMC > HPMC > Eudragit RL100 > Carbopol 940
P > Ethyl Cellulose. The differences
in the swelling might be contributed to the water solubility of the
polymers. SCMC being highly water
soluble and having the maximum tendency to absorb water has swelled a lot. While ethyl cellulose being the least soluble
polymers has swell only to a limited extent that was evident from the reports
obtained for the formulations.
The bio-adhesive
strength of the various formulation were carried out using the method proposed
by Sanjay Garg et al., and Detachment force
measurement was used to measure in-vitro mucoadhesive
capacity of different polymers, it is a modified method developed by Martti Marvola. The result of
the experiment was indicated in the Table IV. it was found that carbopol 940 P had higher mucoadhesive
strength than the other polymers. Increasing the concentration of carbopol 940P also increased the bioadhesive
strength. The bioadhesive
strength of the polymers were found to be carbopol
940P > Eudragit RL100 > SCMC > HPMC >
Ethyl Cellulose.
FTIR study
reveals that there was no interaction took place between the drug and the
polymer.
CONCLUSION:
Formulation R-03
containing Sodium CMC, Carbopol 940P in the ratio 1:2
shows satisfactory mucoadhesive
properties can successfully be employed as a sustain release of Losartan Potassium since it produced adequate swelling and bioadhesion properties due to the hydrophilic nature of
polymers. The dissolution data also
supported that release of drug took place in a control manner over a period of
10 hours.
REFERENCES:
1. Mutthew P. Deacon,
Simon Mcgurk, Clive J. Roberts, Phillip M.
Williams, Saul J.B. Tendler,
Martyn C. Davies, S.S. (Bob) Davis and stephen E. Harding.
“Atomic force microscopy of gastric mucin and chitosan Mucoadhesive
systems”. Biochem.
J. (348) 557-563 (2000).
2. Pramod Kumar T.M.
Shivakumar H. G. and Desai K.G. “ Oral Transmucosal drug delivery systems” a review article, Indian Drugs 41 (2) 63-75 (2004).
3. R. Khanna, S.P. Agrawal; Mucoadhesive drug delivery systems, Indian J. of
Pharmaceutical science, Jan-Feb 1998. 1-10.
4. M. Kerec, M. Bogataj, B. Mugerle, M. Gasperlin, A. Mrhar, “ Mucoadhesion on pig vesical
mucosa Influence of polycarbophil
calcium interactions, “ International Journal of Pharmaceutics, (2002) 241,
135-143.
5. MARTINDALE.The extra
pharmacopoeia 31st edition, The Royal Pharmaceutical society,
(1996), 1372.
6. H.P. Rang,
M.M. Dale, J.M. Ritter. Pharmacology, Churchill livingstone(2003), 5th edition, 297
7. Alfred Goodman
Gilman, The odore W.Rall,
Alan S. Nies and palmer taylor,
“pharmacological Basis of Therapeutics (Eighth Edition), Vol.-I , 1530-1538.
8. Indian
pharmacopoeia, published by the controller of publications, Delhi, Vol-I A-144-146.
9. Martin A. Butastaman P. and Chun A.H.C. Physical Pharmacy, (4th
ed.) B.I Waverly Pvt. Ltd., New Delhi.
481 (1994)
10. Leon Lachman, Lieberman H.A.; The Theory and Practice of
Industrial Pharmacy Third edition, 317
11. K.P.R. Chowdary, B. Suresh, B. Sangeeta
and G. Kamalakara Reddy, “ Design and Evaluation of Diltiazem Mucoadhesive Tablets
for oral controlled Release.” Saudi
pharmaceutical Journal, Vol. 11(4),
201-205 (2003).
12. Susanne Zuleger, Reza Fassihi, Bernhard C. Lippold,
“Polymer particle erosion controlling
drug release. II. swelling
investigations to clarity the release mechanism,” International Journal of
pharmaceutics ( Elsevier) 247, 23-27 (2002)
13. Nafee. NA; Ismail. FA; Boraie. NA; LM, “ Mucoadhesive
delivery systems. Evaluation of Mucoadhesive
polymers for buccal
tablet formulation. Drug-Dev Ind- Pharm ( Drug Development and Industrial Pharmacy); 204; 30 (9); 985-993.
14. Rajesh B.
Gandhi and Joseph R. Robinson, “ Bioadhesion in drug delivery”Indian Journal of Pharmaceutical sciences, 50 (3),
(1998)145-152.
15. Gupta-A; Garg-S; Khar-RK. “Measurement
of bioadhesive strength of mucoadhesive buccal
tablets: design of an in vitro
assembly”. Indian-Drugs;1993; 30(Apr);
152-155.
16. Madhusudan-Rao-Y; Vani-G; Bala-Ramesha-Chary-R. “Design and evaluation of mucoadhesive drug
delivery systems”. Indian-Drugs
(Indian-Drugs); 1998;35(Sep); 558-565.
17. S.P. Vyas and Roop K. Khar, controlled Drug Delivery, concepts and Advances by vallabh prakashan. 265-269.
